Abstract
Lysophosphatidic acid (LPA) refers to a family of simple phospholipids that act as ligands for G protein-coupled receptors. While LPA exerts effects throughout the body in normal physiological circumstances, its pathological role in cancer is of great interest from a therapeutic viewpoint. The numerous LPA receptors (LPARs) are coupled to a variety of G proteins, and more than one LPAR is typically expressed on any given cell. While the individual receptors signal through conventional GPCR pathways, LPA is particularly efficacious in stimulating cancer cell proliferation and migration. This review addresses the mechanistic aspects underlying these pro-tumorigenic effects. We provide examples of LPA signaling responses in various types of cancers, with an emphasis on those where roles have been identified for specific LPARs. While providing an overview of LPAR signaling, these examples also reveal gaps in our knowledge regarding the mechanisms of LPA action at the receptor level. The current understanding of the LPAR structure and the roles of LPAR interactions with other receptors are discussed. Overall, LPARs provide insight into the potential molecular mechanisms that underlie the ability of individual GPCRs (or combinations of GPCRs) to elicit a unique spectrum of responses from their agonist ligands. Further knowledge of these mechanisms will inform drug discovery, since GPCRs are promising therapeutic targets for cancer.
Highlights
Lysophosphatidic acid (LPA) refers to small phospholipids with a single fatty acid substituent with an acyl or alkyl linkage to the glycerol backbone
We provide examples of LPA signaling responses in various types of cancers, with an emphasis on those where roles have been identified for specific LPA receptors (LPARs)
LPA exerts most of its effects by acting as an agonist of G protein-coupled receptors (GPCRs), termed LPA receptors (LPARs), which were first described as binding sites in 1994 [2], and cloned in 1996 [3]
Summary
Lysophosphatidic acid (LPA) refers to small phospholipids with a single fatty acid substituent with an acyl or alkyl linkage to the glycerol backbone. The expression levels of individual receptors do, vary between different types of cells and tissues This provides an opportunity to differentially target LPARs in cancer cells by receptor-selective antagonists. LPARs as potential therapeutic targets and the LPA “axis” in cancer have been reviewed on multiple occasions over the years [1,15,18,20,30,31,32], including in the current Special Issue [33]. LPARs stimulate cell migration and invasion mainly via Gi , and/or G12/13 In this respect, LPARs are no different from hundreds of other GPCRs. the prominent effects of LPA on both cell proliferation and migration raise the question: What makes LPA so special? The discussion will shed light on the need for a more holistic approach to the evaluation of the roles of LPARs and other GPCRs in cancer
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